The discovery that Egr2-deficient mice have hypomyelinated peripheral nerves led to the realization that EGR2 is an essential regulator of the Schwann cell myelination program and, moreover, to the identification of EGR2 mutations in patients with inherited neuropathy. The mutant EGR2 in these patients causes myelinopathy by acting as a dominant inhibitor of the normal EGR2-mediated expression of myelin proteins. Further study demonstrated that NAB proteins, which interact with EGR2 and modulate its transcriptional activity, are also necessary for peripheral nerve myelination. Together, these observations have led us to hypothesize that EGR/NAB complexes are the prime regulators of myelination. Expression profiling experiments using cultured Schwann cells, or sciatic nerves from hypomyelinated mouse mutants and developing mice, or distal segments from transected or crushed sciatic nerves has enabled the identification of a 'myelination-associated gene cluster'. The expression of genes in this cluster is tightly correlated with that of myelin proteins, inferring that they are also involved in the myelination process and regulated by the same transcriptional regulators, which we believe include EGR/NAB complexes. Here, we have outlined experiments aimed at identifying the genetic networks that are regulated by these complexes and are functionally important in myelinating Schwann cells. Having identified candidate target genes by expression profiling, comparative genomic analysis and chromatin immunoprecipitation experiments will now be used to identify genomic loci where EGR2/NAB complexes are bound. Our expression profiling analyses also revealed a novel transcript whose expression in Schwann cells is regulated by EGR2/NAB complexes and is concordant with that of myelin proteins, and whose genomic loci is tightly linked with a CMT neuropathy locus. The function of the MP11 protein encoded by this transcript will be investigated. Finally, we will determine whether EGR2 is necessary and sufficient to mediate the axonal signals that direct Schwann cells to activate the myelination program. [unreadable] [unreadable] [unreadable]